The present invention relates to compounds of the formula I
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83(I)
in which A, B, D, E, F and G have the meanings given below, their physiologically tolerated salts and pharmaceutical preparations comprising these compounds, and to their preparation and use as vitronectin receptor antagonists for the treatment and prophylaxis of diseases which are based on the interaction between vitronectin receptors and their ligands in cell-cell or cell-matrix interaction processes, for example inflammations, cancer, tumor metastasis, cardiovascular disorders such as arteriosclerosis or restenosis, retinopathies and nephropathies, and diseases which are based on an undesirable degree of bone resorption, for example osteoporosis.
Human bones are subject to a continuous, dynamic process of reconstruction involving bone resorption and bone synthesis. These processes are regulated by cell types which are specialized for these purposes. While bone synthesis is based on the deposition of bone matrix by osteoblasts, bone resorption is based on the degradation of bone matrix by osteoclasts. Most bone disorders are based on an imbalance in the equilibrium between bone formation and bone resorption.
Osteoporosis is characterized by a loss of bone matrix. Activated osteoclasts are multinuclear cells which have a diameter of up to 400 xcexcm and which demolish bone matrix. Activated osteoclasts become attached to the surface of the bone matrix and secrete proteolytic enzymes and acids into the so-called sealing zone, i.e. the region between their cell membrane and the bone matrix. The acid environment and the proteases degrade the bone.
Studies have shown that the attachment of osteoclasts to bone is regulated by integrin receptors on the surface of the osteoclast cells.
Integrins are a superfamily of receptors which includes, inter alia, the fibrinogen receptor xcex1IIbxcex23 on the blood platelets and the vitronectin receptor xcex1vxcex23. The vitronectin receptor xcex1vxcex23 is a membrane glycoprotein which is expressed on the surface of a number of cells such as endothelial cells, cells of the smooth musculature of the blood vessels, osteoclasts and tumor cells. The vitronectin receptor xcex1vxcex23 which is expressed on the osteoclast membrane regulates the process of attachment to bone and bone resorption and consequently contributes to osteoporosis. In this connection, xcex1vxcex23 binds to bone matrix proteins, such as osteopontin, bone siloprotein and thrombospontin, which contain the tripeptide motif Arg-Gly-Asp (or RGD).
As vitronectin receptor antagonists, the novel compounds of the formula I inhibit bone resorption by osteoclasts. Bone disorders against which the novel compounds can be employed are, in particular, osteoporosis, hypercalcaemia, osteopenia, e.g. caused by metastases, dental disorders, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, and Paget""s disease. In addition, the compounds of the formula I may be employed for the alleviation, avoidance or therapy of bone disorders which are caused by glucocorticoid, steroid or corticosteroid therapy or by a lack of sex hormone(s). All these disorders are characterized by a loss of bone, due to an imbalance between bone synthesis and bone degradation.
Horton and coworkers describe RGD peptides and an anti-vitronectin receptor antibody (23C6) which inhibit tooth breakdown by osteoclasts and the migration of osteoclasts (Horton et al.; Exp. Cell. Res. 1991, 195, 368). In J. Cell Biol. 1990, 111, 1713, Sato et al. report that echistatin, an RGD peptide from snake venom, is a potent inhibitor of bone resorption in a tissue culture and an inhibitor of the attachment of osteoclasts to the bone. Fischer et al. (Endocrinology, 1993, 132, 1411) showed that echistatin also inhibits bone resorption in vivo in the rat.
The vitronectin receptor xcex1vxcex23 on human cells of the smooth blood vessel musculature of the aorta stimulates the migration of these cells into the neointima, thereby leading finally to artereosclerosis and restenosis following angioplasty (Brown et al., Cardiovascular Res. 1994, 28, 1815).
Brooks et al. (Cell 1994, 79, 1157) show that antibodies against xcex1vxcex23 or xcex1vxcex23 antagonists are able to shrink tumors by inducing the apoptosis of blood vessel cells during angiogenesis. Cheresh et al. (Science 1995, 270, 1500) describe anti-xcex1vxcex23 antibodies or xcex1vxcex23 antagonists which inhibit bFGF-induced angiogenesis processes in the rat eye, a property which could be therapeutically useful in the treatment of retinopathies.
Patent application WO 94/12181 describes substituted aromatic or nonaromatic ring systems, and WO 94/08577 describes substituted heterocycles, which are fibrinogen receptor antagonists and inhibitors of platelet aggregation. EP-A-0 528 586 and EP-A-0 528 587 disclose aminoalkyl-substituted or heterocyclyl-substituted phenylalanine derivatives, and WO 95/32710 discloses aryl derivatives, which are inhibitors of bone resorption due to osteoclasts. WO 96/00574 and WO 96/26190 describe benzodiazepines which are vitronectin receptor antagonists and integrin receptor antagonists, respectively. WO 96/00730 describes fibrinogen receptor antagonists templates, in particular benzodiazepines which are linked to a nitrogen-carrying 5-membered ring, which are vitronectin receptor antagonists. German patent applications P 19629816.4, P 19629817.2 and P 19610919.1 and also EP-A-0 796 855 describe substituted aromatic ring systems or 5-membered ring heterocycles which are vitronectin receptor antagonists.
The present invention relates to compounds of the formula I
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83(I)
in which:
A=A1 or A2, with
A1=R2R3Nxe2x80x94C(xe2x95x90NR2)NR2C(O)xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)NR2C(S)xe2x80x94, R2R3Nxe2x80x94C(xe2x95x90NR2)NR2xe2x80x94S(O)nxe2x80x94, 
xe2x80x83where, in A1 or A2
is a 5-membered to 10-membered monocyclic or polycyclic, aromatic or nonaromatic ring system which contains the grouping 
xe2x80x83and, in addition, can contain from 1 to 4 heteroatoms from the group N, O and S, and, where appropriate, can be substituted, once or more than once, by R12, R13, R14 or R15;
B is a direct linkage, (C1-C8)-alkanediyl, xe2x80x94CR2xe2x95x90CR3xe2x80x94, (C5-C10)-arylene, (C3-C8)-cycloalkylene, xe2x80x94Cxe2x89xa1Cxe2x80x94, which can in each case be substituted, once or twice, by (C1-C8)-alkyl (such as, for example, methyl-phenyl-methyl-, ethyl-CHxe2x95x90CHxe2x80x94, etc.);
D is a direct linkage, (C1-C8)-alkanediyl, (C5-C10)-arylene, xe2x80x94Oxe2x80x94, NR2xe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NRxe2x80x942xe2x80x94, NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CSxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94S(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94NR2xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94Nxe2x95x90CR, xe2x80x94R2Cxe2x95x90Nxe2x80x94, xe2x80x94CH(OH)xe2x80x94, which can in each case be substituted, once or twice, by (C1-C8)-alkyl, xe2x80x94CR2xe2x95x90CR2xe2x80x94 or (C5-C6)-aryl, such as, for example, methyl-phenyl-CHxe2x95x90CHxe2x80x94, ethyl-Oxe2x80x94, etc., with it being possible, if B is a direct linkage, for D also to be a direct linkage or a radical as defined under D, which radical is substituted once or twice, as described under D, and is linked to B by way of one of these substituents.
E a) is a template from the series of fibrinogen receptor antagonists, which template is taken from the following patent applications, patent documents or literature references:
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or
b) is a template which is defined analogously to the templates from the series of fibrinogen receptor antagonists and which is taken from the following patent applications:
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or also is one of those templates which can be derived structurally from the templates which are described in the above patent applications, patent documents and publications;
F is defined like D; 
R2 and R3 are, independently of each other, H, (C1-C10)-alkyl, which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, R8OC(O)R9, R8R8NC(O)R9 or R8C(O)R9;
R4, R5, R6 and R7 are, independently of each other, H, fluorine, OH, (C1-C8)-alkyl, (C3-C14)-cycloalkyl, (C3-C14)-cycloalkyl-(C1-C8)-alkyl, or R8OR9, R8SR9, R8CO2R9, R8OC(O)R9, R8xe2x80x94(C5-C14)-aryl-R9, R8N(R2)R9, R8R8NR9, R8N(R2)C(O)OR9, R8S(O)nN(R2)R9, R8OC(O)N(R2)R9, R8C(O)N(R2)R9, R8N(R2)C(O)N(R2)R9, R8N(R2)S(O)nN(R2)R9, R8S(O)nR9, R8SC(O)N(R2)R9, R8C(O)R9, R8N(R2)C(O)R9 or R8N(R2)S(O)nR9;
R8 is H, (C1-C8)-alkyl, (C3-C14)-cycloalkyl, (C3-C14)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl or (C5-C14)-aryl-(C1-C8)-alkyl, where the alkyl radicals can be substituted, once or more than once, by fluorine;
R9 is a direct linkage or (C1-C8)-alkanediyl;
R10 is C(O)R11, C(S)R11, S(O)nR11, P(O)(R11)n or a four-membered to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, O and S, such as tetrazolyl, imidazolyl, pyrazolyl, oxazolyl or thiadiazolyl;
R11 is OH, (C1-C8)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkoxy, (C5-C14)-aryloxy, (C1-C8)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C5-C14)-aryl-(C1-C8)-alkylcarbonyloxy-(C1-C6)-alkoxy, NH2, mono- or di-((C1-C8)-alkyl)-amino, (C5-C14)-aryl-(C1-C8)-alkylamino, (C1-C8)-dialkylaminocarbonylmethyloxy, (C5-C14)-aryl-(C1-C8)-dialkylaminocarbonylmethyloxy or (C5-C14)-arylamino or the radical of an L-amino acid or D-amino acid;
R12, R13, R14 and R15 are, independently of each other, H, (C1-C10)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C12)-cycloalkyl, (C3-C12)-cycloalkyl-(C1-C8)-alkyl, (C5-C14)-aryl, (C5-C14)-aryl-(C1-C8)-alkyl, H2N, R8ONR9, R8OR9, R8OC(O)R9, R8R8NR9, R8xe2x80x94(C5-C14)-aryl-R9, HOxe2x80x94(C1-C8)-alkyl-N(R2)R9, R8N(R2)C(O)R9, R8C(O)N(R2)R9, R8C(O)R9, R8R8Nxe2x80x94C(xe2x95x90NR)xe2x80x94NR2, R2R3Nxe2x80x94C(xe2x95x90NR2), xe2x95x90O, or xe2x95x90S;
xe2x80x83where two adjacent substituents from R12 to R15 can also together be xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94 or xe2x80x94OC(CH3)Oxe2x80x94;
n is 1 or 2;
p and q are, independently of each other, 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts
with compounds being excepted in which E
a) is a 6-membered aromatic ring system which can contain up to 4 N atoms and which can be substituted by from 1 to 4 identical or different arbitrary substituents, or
b) is 4-methyl-3-oxo-2,3,4,5-tetrahydro-1-H-1,4-benzodiazepine.
A template from the series of fibrinogen receptor antagonists is understood to mean the central part of the molecular structure (of a fibrinogen receptor antagonist) to which, in the case of the fibrinogen receptor antagonists, a basic group and an acidic group are linked by way of spacers, with the basic and/or acidic group being present in protected form (prodrug) where appropriate.
In the fibrinogen receptor antagonists, the basic group is generally an N-containing group, such as amidine or guanidine, while the acidic group is generally a carboxyl function, with it being possible for the basic group and the acidic group to be present in each case in protected form.
A fibrinogen receptor antagonist is an active compound which inhibits the binding of fibrinogen to the blood platelet receptor GPIIbIIIa.
A fibrinogen receptor antagonist comprises a central part (template) to which a basic group and an acidic group are linked by way of spacers, with the basic group and/or acidic group being present in protected form (prodrug), where appropriate.
Alkyl radicals may be straight-chain or branched. This also applies if they carry substituents or appear as the substituents of other radicals, for example in alkoxy, alkoxycarbonyl or aralkyl radicals. Examples of suitable (C1-C10)-alkyl radicals are: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, decyl, isopropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,3,5-trimethylhexyl, sec-butyl and tert-pentyl. Preferred alkyl radicals are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
Alkenyl and alkynyl radicals may also be straight-chain or branched. Examples of alkenyl radicals are vinyl, 1-propenyl, allyl, butenyl and 3-methyl-2-butenyl, while examples of alkynyl radicals are ethynyl, 1-propynyl or propargyl.
Cycloalkyl radicals may be monocyclic or polycyclic, e.g. bicyclic or tricyclic. Examples of monocyclic cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclododecyl which, however, can also be substituted by, for example, (C1-C4)-alkyl. 4-Methylcyclohexyl and 2,3-dimethylcyclopentyl may be mentioned as examples of substituted cycloalkyl radicals.
Cyclodecane and cyclododecane are examples of parent substances of the monocyclic (C10-C14)-cycloalkyl radicals in R4, R5, R6 and R7.
Bicyclic and tricyclic cycloalkyl radicals may be unsubstituted or substituted, in any suitable position, by one or more oxo groups and/or one or more identical or different (C1-C4)-alkyl groups, e.g. methyl groups or isopropyl groups, preferably methyl groups. The free bond of the bicyclic or tricyclic radical can be located in any position in the molecule; the radical can consequently be bonded via a bridgehead atom or via an atom in a bridge. The free bond can also be located in any stereochemical position, for example in an exo position or an endo position.
An example of a bicyclic ring system is decalin (decahydronaphthalene), while an example of a system substituted by an oxo group is 2-decanone.
Examples of parent substances of bicyclic ring systems. are norbornane (=bicyclo[2.2.1]heptane), bicyclo[2.2.2]octane and bicyclo[3.2.1]octane. An example of a system which is substituted by an oxo group is camphor (=1,7,7-trimethyl-2-oxobicyclo[2.2.1]heptane).
Examples of parent substances of tricyclic systems are twistane (=tricyclo[4.4.0.03,8]decane, adamantane (=tricyclo[3.3.1.13,7]decane), noradamantane (=tricyclo[3.3.1.03,7]-nonane), tricyclo[2.2.1.02,6]heptane, tricyclo[5.3.2.04,9]dodecane, tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]tridecane.
Examples of parent substances of tricyclic (C10-C14)-cycloalkyl radicals in R4, R5, R6 and R7 are twistane (=tricyclo[4.4.0.0.3,8]decane, adamantane (=tricyclo[3.3.1.1.3,7]nonane), tricyclo[5.3.2.04,9]dodecane, tricyclo[5.4.0.02,9]undecane or tricyclo[5.5.1.03,11]tridecane.
Halogen is fluorine, chlorine, bromine or iodine.
Examples of 6-membered aromatic ring systems are phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl and tetrazinyl.
Aryl is, for example, phenyl, naphthyl, biphenylyl, anthryl or fluoroenyl, with 1-naphthyl, 2-naphthyl and, in particular, phenyl being preferred. Aryl radicals, in particular phenyl radicals, may be substituted, once or more than once, preferably once, twice or three times, by identical or different radicals from the group consisting of (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, such as fluorine, chlorine and bromine, nitro, amino, trifluoromethyl, hydroxyl, methylenedioxy, xe2x80x94OCH2CH2Oxe2x80x94, xe2x80x94OC(CH3)2Oxe2x80x94, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, (R17O)2P(O), (R17O)2P(O)xe2x80x94Oxe2x80x94 or tetrazolyl, where R17 is H, (C1-C10)-alkyl, (C6-C14)-aryl or (C6-C14)-aryl-(C1-C8)-alkyl.
In monosubstituted phenyl radicals, the substituent can be located in the 2, 3 or 4 position, with the 3 and 4 positions being preferred. If phenyl is substituted twice, the substituents can be in the 1, 2 or 1, 3 or 1, 4 positions relative to each other. The two substituents in phenyl radicals which are substituted twice are preferably arranged in the 3 and 4 positions, based on the linkage site.
Aryl groups can also be monocyclic or polycyclic aromatic ring systems in which from 1 to 5 carbon atoms can be replaced by from 1 to 5 heteroatoms, such as 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolinyl or xcex2-carbolinyl, or a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of these radicals. These heterocycles can be substituted by the same substituents as the abovementioned carbocyclic aryl systems.
Of these aryl groups, preference is given to monocyclic or bicyclic aromatic ring systems which have from 1 to 3 heteroatoms from the group N, O and S and which can be substituted by from 1 to 3 substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy, F, Cl, NO2, NH2, CF3, OH, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy or benzyl.
In this context, particular preference is given to monocyclic or bicyclic aromatic 5-membered to 10-membered ring systems which have from 1 to 3 heteroatoms from the group N, O and S and which can be substituted by from 1 to 2 substituents from the group consisting of (C1-C4)-alkyl, (C1-C4)-alkoxy, phenyl, phenoxy, benzyl or benzyloxy.
L- or D-amino acids can be natural or unnatural amino acids. xcex1-Amino acids are preferred. The following may be mentioned by way of example (cf. Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Volume XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974):
Aad, Abu, xcex3Abu, ABz, 2ABz, xcex5Aca, Ach, Acp, Adpd, Ahb, Aib, xcex2Aib, Ala, xcex2Ala, xcex94Ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hIle, hLeu, hLys, hMet, hphe, hpro, hser, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, xcex2Lys, xcex94Lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, xcex94Pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, xcex2Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), neopentylglycine (Npg), cyclohexylglycine (Chg), cyclohexylalanine (Cha), 2-thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl)-2-phenyl-aminoacetic acid and 2-(p-chlorophenyl)aminoacetic acid;
and also:
pyrrolidine-2-carboxylic acid; piperidine-2-carboxylic acid; 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; decahydroisoquinoline-3-carboxylic acid; octahydroindole-2-carboxylic acid; decahydroquinoline-2-carboxylic acid; octahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2-azabicyclo[2.2.2]octane-3-carboxylic acid; 2-azabicyclo[2.2.1]heptane-3-carboxylic acid; 2-azabicyclo[3.1.0]hexane-3-carboxylic acid; 2-azaspiro[4.4]nonane-3-carboxylic acid; 2-azaspiro[4.5]decane-3-carboxylic acid; spiro(bicyclo[2.2.1]heptane)-2,3-pyrrolidine-5-carboxylic acid; spiro(bicyclo[2.2.2]octane)-2,3-pyrrolidine-5-carboxylic acid; 2-azatricyclo[4.3.0.16,9]decane-3-carboxylic acid; decahydrocyclohepta[b]pyrrole-2-carboxylic acid; decahydrocycloocta[c]pyrrole-2-carboxylic acid; octahydrocyclopenta[c]pyrrole-2-carboxylic acid; octahydroisoindole-1-carboxylic acid; 2,3,3a,4,6a-hexahydrocyclopenta[b]pyrrole-2-carboxylic acid; 2,3,3a,4,5,7a-hexahydroindole-2-carboxylic acid; tetrahydrothiazole-4-carboxylic acid; isoxazolidine-3-carboxylic acid; pyrazolidine-3-carboxylic acid and hydroxypyrrolidine-2-carboxylic acid, all of which can optionally be substituted (see the following formulae): 
The heterocycles on which the abovementioned radicals are based are disclosed, for example, in U.S. Pat. No. 4,344,949; U.S. Pat. No. 4,374,847; U.S. Pat. No. 4,350,704; EP-A 29,488; EP-A 31,741; EP-A 46,953; EP-A 49,605; EP-A 49,658; EP-A 50,800; EP-A 51,020; EP-A 52,870; EP-A 79,022; EP-A 84,164; EP-A 89,637; EP-A 90,341; EP-A 90,362; EP-A 105,102; EP-A 109,020; EP-A 111,873; EP-A 271,865 and EP-A 344,682.
In addition, the amino acids can also be present as esters or amides, such as methyl esters, ethyl esters, isopropyl esters, isobutyl esters, tert-butyl esters, benzyl esters, unsubstituted amide, ethylamide, semicarbazide or xcfx89-amino-(C2-C8)-alkylamide.
Functional groups in the amino acids may be present in protected form. Suitable protecting groups, such as urethane protecting groups, carboxyl protecting groups and side-chain protecting groups, are described in Hubbuch, Kontakte (Merck) 1979, No. 3, pages 14 to 23 and in Bxc3xcllesbach, Kontakte (Merck) 1980, No. 1, pages 23 to 35. Those which may, in particular, be mentioned are: Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tert-butyl, OBzl, ONbzl, OMbzl, Bzl, Mob, Pic, Trt.
Physiologically tolerated salts of the compounds of the formula I are, in particular, pharmaceutically utilizable or nontoxic salts. Such salts are formed, for example, from compounds of the formula I which contain acidic groups, e.g. carboxyl, with alkali metals or alkaline earth metals, such as Na, K, Mg and Ca, and also with physiologically tolerated organic amines, such as triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. Compounds of the formula I which contain basic groups, e.g. an amino group, an amidino group or a guanidino group, form salts with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic acids or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, methanesulfonic acid or p-toluenesulfonic acid.
The novel compounds of the formula I may contain optically active carbon atoms, which, independently of each other, can have R or S configurations, and they consequently may be present in the form of pure enantiomers or pure diastereomers or in the form of enantiomeric mixtures or diastereomeric mixtures. The present invention relates both to pure enantiomers and enantiomeric mixtures in all proportions and to diastereomers and diastereomeric mixtures in all proportions.
The novel compounds of the formula I may be present, independently of each other, as E/Z isomeric mixtures. The present invention relates both to pure E and Z isomers and to E/Z isomeric mixtures. Diastereomers, including E/Z isomers, can be separated into the individual isomers by means of chromatography. Racemates can be separated into the two enantiomers either by means of chromatography on chiral phases or by means of racemate resolution. The present invention moreover includes all solvates of compounds of the formulae I and Ia, for example hydrates or adducts with alcohols, and also derivatives of the compounds of the formulae I and Ia, for example esters, prodrugs and metabolites, which act like the compounds of the formulae I and Ia.
In addition to this, the novel compounds of the formula I may contain mobile hydrogen atoms, that is they may be present in different tautomeric forms. The present invention also relates to all these tautomers.
Preference is given to compounds of the formula I which are selective vitronectin receptor antagonists, particularly in relation to the fibrinogen receptor, i.e. which are stronger inhibitors of the vitronectin receptor than of the fibrinogen receptor.
Preference is given, in particular, to compounds of the formula I which are selective vitronectin receptor antagonists and in which the distance between R10 and the first N atom in A1 is from 12 to 13, and in A2 from 11 to 12, covalent bonds along the shortest route between these atoms, as depicted below, by way of example, for 
Preference is also given to compounds of the formula I in which at least one radical from the group R4, R5, R6 and R7 is a lipophilic radical.
Examples of lipophilic radicals in the group R4, R5, R6 and R7 are neopentyl, cyclohexyl, adamantyl, cyclohexyl-(C1-C8)-alkyl, adamantyl-(C1-C8)-alkyl, phenyl, naphthyl, phenyl-(C1-C8)-alkyl, naphthyl-(C1-C8)-alkyl, cyclohexylmethylcarbonylamino, 1-adamantylmethyloxycarbonylamino or benzyloxycarbonylamino, or, generally, radicals in which R8 is, for example, neopentyl, cyclohexyl, adamantyl, cyclohexyl-(C1-C8)-alkyl, adamantyl-(C1-C8)-alkyl, phenyl, naphthyl, phenyl-(C1-C8)-alkyl or naphthyl-(C1-C8)-alkyl.
Preference is furthermore given to compounds of the formula I in which:
A=A1 or A2, with 
where, in A1 or A2
xe2x80x83is a 5-membered to 10-membered monocyclic or polycyclic, aromatic or nonaromatic ring system which contains the grouping 
xe2x80x83and, in addition, can contain from 1 to 4 heteroatoms from the group N, O and S and, where appropriate, can be substituted, once or more than once, by R12, R13, R14 and R15;
B is a direct linkage, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, (C1-C6)-alkanediyl, (C5-C8)-arylene, (C5-C6)-cycloalkylene, xe2x80x94CR2xe2x95x90CR3 xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, which can in each case be substituted, once or twice, by (C1-C6)-alkyl;
D is a direct linkage, (C1-C8)-alkanediyl, (C5-C10)-arylene, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NRxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Nxe2x95x90CR2xe2x80x94, xe2x80x94R2Cxe2x95x90Nxe2x80x94, which can in each case be substituted, once or twice, by (C1-C8)-alkyl, xe2x80x94CR2xe2x95x90CR3xe2x80x94 or (C1-C6)-aryl, with it being possible, if B is a direct linkage, for D also to be a direct linkage or a radical as defined under D, which radical is substituted once or twice, as described under D, and is linked to B by way of one of these substituents;
E is a template from the fibrinogen receptor antagonist group, which template is taken from:
WO 93/08174, Oct. 15, 1991, Blackburn, B. K., et al.
U.S. Pat. No. 5,250,679, Oct. 5, 1993, Blackburn, B. K., et al.
U.S. Pat. No. 5,403,836, Apr. 4, 1995, Blackburn, B. K., et al.
WO 95/04057, Feb. 9, 1995, Blackburn, B. K., et al.
EP 0 655 439, Nov. 9, 1994, Denney, M. L., et al.
WO 94/18981, Sep. 1, 1994, Claremon, D. A., et al.
WO 94/08962, Apr. 28, 1994, Harmann, G. D., et al.
EP 0 668 278, Feb. 14, 1995, Juraszyk, H., et al.
WO 94/12478, Jun. 9, 1994, Keenan, B. Mc. C., et al.
EP 0 531 883, Sep. 3, 1992, Austel, V., et al.
F is defined like D; 
R and R3 are, independently of each other, H, (C1-C10)-alkyl, which is optionally substituted, once or more than once, by fluorine, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkyl, R8OC(O)R9, R8R8NC(O)R9 or R8(O)R9;
R4, R5, R6 and R7 are, independently of each other, H, fluorine, OH, (C1-C8)-alkyl, (C5-C14)-cycloalkyl, (C5-C14)-cycloalkyl-(C1-C8)-alkyl, or R8OR9, R8SR9, R8CO2R9, R8OC(O)R9, R8xe2x80x94(C5-C14)-aryl-R9, R8N(R2)R9, R8R8NR9, R8N(R2)C(O)OR9, R8S(O)N(R2)R9, R8OC(O)N(R2)R9, R8C(O)N(R2)R9, R6N(R2)C(O)N(R2)R9, R8N(R2)S(O)nN(R2)R9, R8S(O)nR9, R8SC(O)N(R2)R9, R8C(O)R9, R8N(R2)C(O)R9 or R8N(R2)S(O)nR9;
R8 is H, (C1-C6)-alkyl, (C5-C14)-cycloalkyl, (C5-C14)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl or (C5-C12)-aryl-(C1-C6)-alkyl, where the alkyl radicals can be substituted, once or more than once, by fluorine;
R9 is a direct linkage or (C1-C6)-alkanediyl;
R10 is C(O)R11, C(S)R11, S(O)nR11, P(O)(R11)n or a four-membered to eight-membered, saturated or unsaturated heterocycle which contains 1, 2, 3 or 4 heteroatoms from the group N, O and S;
R1 is OH, (C1-C6)-alkoxy, (C5-C12)-aryl-(C1-C6)-alkoxy, (C5-C12)-aryloxy, (C1-C6)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C5-C12)-aryl-(C1-C6)-alkylcarbonyloxy-(C1-C6)-alkoxy, NH2, mono- or di-((C1-C6)-alkyl)-amino, (C5-C12)-aryl-(C1-C6)-alkylamino, (C1-C6)-dialkylaminocarbonylmethyloxy;
R12, R13, R14 and R15 are, independently of each other, H, (C1-C8)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, (C5-C12)-aryl, (C5-C12)-aryl-(C1-C6)-alkyl, H2N, R8ONR9, R8OR9, R8OC(O)R9, R8xe2x80x94(C5-C12)-aryl-R9, R8R8NR9, HOxe2x80x94(C1-C8)-alkyl-N(R2)R9, R8N(R2)C(O)R9, R8C(O)N(R2)R9, R8C(O)R9, R2R3Nxe2x80x94C(xe2x95x90NR2), R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2, xe2x95x90O or xe2x95x90S;
xe2x80x83where two adjacent substituents from R12 to R15 can also together be xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94 or xe2x80x94OC(CH3)2Oxe2x80x94;
n is 1 or 2;
p and q are, independently of each other, 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts.
Particular preference is given to compounds of the formula I in which:
A=A1 or A2, with 
xe2x80x83where, in A1 or A2 the radical 
xe2x80x83is a radical from the group 
xe2x80x83where Y=NR2, O or S;
B is a direct linkage, (C1-C6)-alkanediyl, (C5-C6)-arylene, xe2x80x94CR2xe2x95x90CR3xe2x80x94, which can in each case be substituted, once or twice, by (C1-C6)-alkyl;
D is a direct linkage, (C1-C6)-alkanediyl, (C5-C6)-arylene, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(S)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94 or xe2x80x94CR2xe2x95x90CR3xe2x80x94 which can in each case be substituted, once or twice, by (C1-C6)-alkyl, xe2x80x94CHxe2x95x90CHxe2x80x94 or phenyl; with it being possible, if B is a direct linkage, for D also to be a direct linkage or a radical as defined under D, which radical is substituted once or twice, as described under D, and is linked to B by way of one of these substituents;
E a) is a template from WO 93/08174, U.S. Pat. No. 5,250,679, U.S. Pat. No. 5,403,836 or U.S. Pat. No. 5,565,449, specifically: 
where R1a, R2a, R20a, R21a and R22a are defined like R1,R2 R20, R21 and R22 in U.S. Pat. No. 5,403,836, column 249, lines 9-22; and column 252, line 66 to column 253, line 68, and consequently:
R1a and R2a are, independently of each other, from one to three groups from the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxyl, mercapto or sulfonamido, or an optionally substituted radical from the group consisting of C1-C12-alkyl, C2-C12-alkenyl, C3-C12-alkynyl, C3-C12-cycloalkyl, C6-C14-aryl, C6-C10-aryl-C1-C8-alkyl, C1-C12-alkyloxy, C6-C14-aryloxy and C1-C12-acylamino, where the substituents are a radical from the group consisting of halogen, cyano, azido, nitro, hydroxyl, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, C1-C4-alkoxy, phenyl and phenoxy;
R20a is hydrogen, halogen (fluorine, chlorine, bromine or iodine), C1-C4-alkoxy, C1-C4-alkyl, phenyl, benzyl or halogen-C1-C4-alkyl,
R21a and R22a are, independently of each other,
xe2x80x831. hydrogen
xe2x80x832. (C1-C12)-alkyl
xe2x80x833. (C6-C14)-aryl,
xe2x80x834. (C3-C14)-cycloalkyl,
xe2x80x835. (C1-C12)-alkyl-(C6-C14)-aryl,
xe2x80x836. (C1-C12)-alkyl-(C3-C14)-cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide; phosphonate; C1-C6-alkyl; C6-C14-aryl; benzyl; C3-C14-cycloalkyl; COR24a or CONR25R26; where
R24a is a radical from the group consisting of C1-C8-alkoxy; C3-C12-alkenoxy; C6-C12-aryloxy; di-C1-C8-alkylamino-C1-C8-alkoxy; acylamino-C1-C8-alkoxy, such as acetylaminoethoxy, nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; or C6-C12-aryl-C1-C8-alkoxy, where the aryl group can be optionally substituted by from one to three radicals selected from the group consisting of nitro, halogen, C1-C4-alkoxy, amino, hydroxyl, hydroxy-C2-C8-alkoxy or dihydroxy-C3-C8-alkoxy;
R25 and R26 are, independently of each other,
xe2x80x83hydrogen, C1-C10-alkyl, C3-C10-alkenyl, C6-C14-aryl or C1-C6-alkyl-C6-C10-aryl, or
R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;
xe2x80x837. Q2xe2x80x94L31, where
Q2 is hydrogen or Q1; and
L3 is a chemical bond, L1 or L2;
xe2x80x83Q1 is a substituted or unsubstituted, positively charged, nitrogen-containing radical,
xe2x80x83L1 is a divalent radical which contains from 3 to 9 methylene groups, where from one to all the methylene groups can be replaced with one or more alkene groups, alkyne groups, aryl groups or functional groups containing heteroatoms from the group consisting of N, O or S, and
xe2x80x83L2 is an optionally substituted, divalent radical;
where preferred radicals for Q1, L1 and L2 are those radicals as described in U.S. Pat. No. 5,403,836 in column 249, line 27 to column 251, line 6 (Q1), column 251, line 7 to column 252, line 18 (L1) and column 252, lines 19-45 (L2);
and R22b is defined like R2 in U.S. Pat. No. 5,565,449, column 296, line 38 to column 297, line 38, and is:
xe2x80x831. hydrogen
xe2x80x832. (C1-C12)-alkyl
xe2x80x833. (C6-C14)-aryl,
xe2x80x834. (C3-C14)-cycloalkyl,
xe2x80x835. (C1-C12)-alkyl-(C6-C14)-aryl,
xe2x80x836. (C1-C12)-alkyl-(C3-C14)-cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide; phosphonate; C1-C6-alkyl; C6-C14-aryl; benzyl; C3-C14-cycloalkyl; COR24a or CONR25R26; where
R24a is a radical from the group consisting of C1-C8alkoxy; C3-C12-alkenoxy; C6-C12-aryloxy; di-((C1-C8)-alkyl)-amino-C1-C8-alkoxy; acylamino-C1-C8-alkoxy, such as acetylaminoethoxy, nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; or C6-C12-aryl-C1-C8-alkoxy, where the aryl group can optionally be substituted by from one to three radicals selected from the group consisting of nitro, halogen, C1-C4-alkoxy, amino, hydroxyl, hydroxy-C2-C8-alkoxy or dihydroxy-C3-C8-alkoxy;
R25 and R26 are, independently of each other,
xe2x80x83hydrogen, C1-C10-alkyl, C3-C10-alkenyl, C6-C14-aryl or C1-C6-alkyl-C6-C10-aryl, or
R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;
xe2x80x837. Q2xe2x80x94L31, where
Q2 is hydrogen or Q1; and
L3 is a chemical bond, L1 or L2;
xe2x80x83Q1 is a substituted or unsubstituted, positively charged, nitrogen-containing radical,
xe2x80x83L1 is a divalent radical which contains from 3 to 9 methylene groups, where from one to all the methylene groups can be replaced with one or more alkene radicals, alkyne radicals, aryl radicals or functional groups containing heteroatoms from the group consisting of N, O or S, and
xe2x80x83L2 is an optionally substituted, divalent radical;
where preferred radicals for Q1, L1 and L2 are those radicals as described in U.S. Pat. No. 5,403,836 in column 289, line 9 to column 293, line 17 (Q1), column 293, line 18 to column 295, line 28 (L1) and column 295, line 29 to column 296, line 11 (L2);
or b)is a template from WO 95/04057, specifically: 
where R1b and R2b are defined like R1 and R2 in U.S. Pat. No. 5,403,836, column 249, lines 9-22; and are:
R1b and R2b are, independently of each other, from one to three groups from the series consisting of hydrogen, halogen, cyano, carboxamido, carbamoyloxy, formyloxy, formyl, azido, nitro, ureido, thioureido, hydroxyl, mercapto or sulfonamido, or an optionally substituted radical from the group consisting of C1-C12-alkyl, C2-C12-alkenyl, C3-C12-alkynyl, C3-C12-cycloalkyl, C6-C14-aryl, C6-C10-aryl-C1-C8-alkyl, C1-C12-alkyloxy, C6-C14-aryloxy and C1-C12-acylamino, where the substituents are a radical from the group consisting of halogen, cyano, azido, nitro, hydroxyl, mercapto, sulfonamido, ureido, thioureido, carboxamido, carbamoyloxy, formyloxy, formyl, C1-C4-alkoxy, phenyl and phenoxy; and
R25b and R26b are defined like R25 and R26 in U.S. Pat. No. 5,565,449 and:
R25b and R26b are, independently of each other, hydrogen, C1-C10-alkyl, C3-C10-alkenyl, C6-C14-aryl or C1-C6-alkyl-C6-C10-aryl, or R25b and R26b together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;
or c) is a template from EP-A 0 655 439, specifically 
xe2x80x83where
(R2)p is bonded to one or more carbon atoms of the 6-membered ring and is, independently of each other, a radical from the group consisting of H, alkyl, halogen-substituted alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl, hydroxyl, alkoxy, aralkoxy, carbamyl, amino, substituted amino, acyl, cyano, halogen, nitro and sulfo;
R is (C1-C4)-alkyl
p is an integer from 1 to 3,
or d) is a template from WO 94/12478, specifically 
where R3 is hydrogen, (C1-C6)-alkyl or aryl-C1-C6-alkyl,
or e) is a template from WO94/18981, specifically 
xe2x80x83in which V is CR7a or N, and
Da is CH2, CH2xe2x80x94CH2, CH2C(R7a)2CH2 or 
xe2x80x83in which X is CR3a or N,
where R3a is CN, C(O)N(R7a)R8a, 
xe2x80x83in which V is CR7a or N, and
Da is CH2, CH2xe2x80x94CH2, CH2C(R7a)2CH2 or 
xe2x80x83in which X is CR3a or N, in which
R3a is CN, C(O)N(R7a)R8a, 
xe2x80x83where Y3 is O or H2, and
R7a is hydrogen; C1-C4-alkyl which is optionally substituted by OH or (C1-C4)-alkoxy; C2-C6-alkenyl which is optionally substituted by (C1-C4)-alkoxy; or OH (C1-C4)-alkylaryl; or aryl which is optionally substituted by identical or different radicals from the group consisting of halogen, (C1-C4)-alkoxy, hydroxyl or (C1-C4)-alkyl,
R8a is hydrogen or C1-C4-alkyl,
xe2x80x83n is an integer from 0 to 7, and
xe2x80x83nxe2x80x2 is an integer from 0 to 3;
or f) is a template from EP-A 0531 883, specifically 
xe2x80x83where:
Xxe2x80x2 is an oxygen, sulfur or nitrogen atom or an xe2x80x94NR2bxe2x80x94 group, where
R2b is a hydrogen atom, a straight-chain or branched alkyl group having from 1 to 15 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having in each case from 3 to 10 carbon atoms, where the double bond or triple bond cannot connect directly to the nitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each case from 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, an alkyl group having from 2 to 6 carbon atoms which is substituted, from the xcex2 position to the nitrogen atom of the xe2x80x94NR2bxe2x80x94 group onwards, by an R3bOxe2x80x94, (R3b)2Nxe2x80x94, R4bCOxe2x80x94NR3bxe2x80x94, alkylsulfonyl-NR3b, arylsulfonyl-NR3bxe2x80x94, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R5b group, or an alkyl group having from 1 to 6 carbon atoms which is substituted by one or two aryl groups, R6bOCOxe2x80x94, (R3b)2NCOxe2x80x94, R5bxe2x80x94COxe2x80x94, R3bOxe2x80x94CO-alkylene-NR3xe2x80x94COxe2x80x94, (R3b)2Nxe2x80x94CO-alkylene-NR3bCOxe2x80x94 or R5bCO-alkylene-NR3bxe2x80x94COxe2x80x94 group, in which R3b and R5b are defined as indicated below and R6bis a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms or an aralkyl group,
Yxe2x80x2 is an NO-group, a nitrogen atom or a methine group which is optionally substituted by an alkyl group,
Z1, Z2, Z3 und Z4, which can be identical or different, are methine groups, carbon atoms, imino groups or nitrogen atoms, where at least one of the radicals Z1 to Z4 has to contain a carbon atom, and one or two methine groups which are adjacent to a nitrogen atom can in each case be replaced by carbonyl groups,
Z5 and Z6 are in each case a carbon atom, or else one of the radicals Z5 or Z6 is a nitrogen atom and the other of the radicals Z5 or Z6 is a carbon atom,
xe2x80x83R3b is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group,
R4b is a hydrogen atom, an alkyl or alkoxy group having in each case from 1 to 6 carbon atoms, or an aryl or aralkyl group having from 1 to 6 carbon atoms in the alkyl moiety, and
R5b is an azetidino, pyrrolidino, hexamethylenimino or heptamethylenimino group or a piperidino group in which the methylene group in the 4 position can be replaced by an oxygen atom, by a sulfenyl, sulfinyl or sulfonyl group, or by an imino group which is substituted by an R3, R4COxe2x80x94, alkylsulfonyl or arylsulfonyl group, where R3 and R4 are defined as mentioned above;
F is a direct linkage, (C1-C6)-alkanediyl, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94CR2xe2x95x90CR3xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94 which can in each case be substituted, once or twice, by (C1-C6)-alkyl; 
R2 and R3 are, independently of each other, H, (C1-C6)-alkyl which is optionally substituted, once or more than once, by fluorine, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C4)-alkyl, R8OC(O)R9, R8R8NC(O)R9 or R8C(O)R9;
R4, R5, R6 and R7 are, independently of each other, H, fluorine, OH, (C1-C6)-alkyl, (C5-C14)-cycloalkyl, (C5-C14)-cycloalkyl-(C1-C6)-alkyl, or R8OR9, R8CO2R9, R8OC(O)R9, R8xe2x80x94(C5-C10)-aryl-R9, R8NHR9, R8R8NR9, R8NHC(O)OR9, R8S(O)nNHR9, R8OC(O)NHR9, R8C(O)NHR9, R8C(O)R9, R8NHC(O)NHR9, R8NHS(O)nNHR9, R8NHC(O)R9 or R8NHS(O)nR9, where at least one radical from the group R4, R5, R6 and R7 is a lipophilic radical, such as benzyloxycarbonylamino, cyclohexylmethylcarbonylamino etc.;
R8 is H, (C1-C6)-alkyl, (C5-C14)-cycloalkyl, (C5-C14)-cycloalkyl-(C1-C4)-alkyl, (C5-C10)-aryl or (C5-C10)-aryl-(C1-C4)-alkyl, where the alkyl radicals can be substituted by from 1 to 6 fluorine atoms;
R9 is a direct linkage or (C1-C6)-alkanediyl;
R10 is C(O)R11;
R11 is OH, (C1-C6)-alkoxy, (C5-C10)-aryl-(C1-C6)-alkoxy, (C5-C10)-aryloxy, (C1-C6)-alkylcarbonyloxy-(C1-C4)-alkoxy, (C5-C10)-aryl-(C1-C4)-alkylcarbonyloxy-(C1-C4)-alkoxy, NH2 or mono- or di-(C1-C6-alkyl)-amino;
R12 is H, (C1-C6)-alkyl which is optionally substituted, once or more than once, by fluorine, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C4)-alkyl, (C5-C10)-aryl, (C5-C10)-aryl-(C1-C4)-alkyl, H2N, R8OR9, R8OC(O)R9, R8xe2x80x94(C5-C10)-aryl-R9, R8R8NR9, R8NHC(O)R9, R8C(O)NHR9, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94, H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94 or xe2x95x90O;
xe2x80x83where two adjacent substituents R12 can together also be xe2x80x94OCH2Oxe2x80x94 or xe2x80x94OCH2CH2Oxe2x80x94;
n is 1 or 2; and
p and q are, independently of each other, 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts.
Very particular preference is given to compounds of the formula I in which:
A=A1 or A2, with 
where, in A1 or A2 the radical 
xe2x80x83is a radical from the group 
B is (C1-C4)-alkanediyl, phenylene, pyridinediyl, thiophenediyl, furandiyl or xe2x80x94CR2xe2x95x90CR3xe2x80x94, which can in each case be substituted, once or twice, by (C1-C4)-alkyl,
D is a direct linkage, (C1-C4)-alkanediyl, xe2x80x94Oxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94NR2COxe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94CR2xe2x95x90CR3xe2x80x94, which can in each case be substituted, once or twice, by (C1-C4)-alkyl.
E a) is a template from WO 93/08174, U.S. Pat. No. 5,250,679, U.S. Pat. No. 5,403,836 or U.S. Pat. No. 5,565,449, specifically: 
xe2x80x83where R1a, R20a, R21a, R22a and R22b are in this case:
R1a is, independently of each other, from one to three groups from the series consisting of hydrogen and halogen (fluorine, chlorine, bromine or iodine);
R20a is hydrogen;
R21a and R22a are, independently of each other,
1. hydrogen
2. (C1-C6)-alkyl
3. (C6-C12)-aryl,
4. (C6-C12)-cycloalkyl,
5. (C1-C6)-alkyl-(C6-C12)-aryl,
6. (C1-C6)-alkyl-(C6-C12)-cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of fluorine, chlorine, hydroxyl, hydroxamate, sulfonamide, (C1-C6)-alkyl, (C6-C12)-aryl, benzyl or (C6-C12)-cycloalkyl;
R22b is
1. hydrogen
2. (C1-C12)-alkyl
3. (C6-C14)-aryl,
4. (C3-C14)-cycloalkyl,
5. (C1-C12)-alkyl-(C6-C14)-aryl,
6. (C1-C12)-alkyl-(C3-C14)-cycloalkyl, where the radicals defined under 2. to 6. can be substituted by one or more radicals from the group consisting of halogen (fluorine, chlorine, bromine or iodine); nitro; hydroxyl; carboxyl; tetrazole; hydroxamate; sulfonamide; trifluoroimide; phosphonate; C1-C6-alkyl; C6-C14-aryl; benzyl; C3-C14-cycloalkyl; COR24a or CONR25R26; where
R24a is a radical from the group consisting of C1-C8-alkoxy; C3-C12-alkenoxy; C6-C12-aryloxy; di-C1-C9-alkylamino-C1-C8-alkoxy; acylamino-C1-C8-alkoxy, such as acetylaminoethoxy, nicotinoylaminoethoxy, succinamidoethoxy or pivaloylethoxy; or C6-C12-aryl-C1-C8-alkoxy, where the aryl group can be optionally substituted by from one to three radicals selected from the group consisting of nitro, halogen, C1-C4-alkoxy, amino, hydroxyl, hydroxy-C2-C8-alkoxy and dihydroxy-C3-C8-alkoxy;
R25 and R26 are, independently of each other,
xe2x80x83hydrogen, C1-C10-alkyl, C3-C10-alkenyl, C1-C14-aryl or C1-C6-alkyl-C6-C10-aryl, or
R25 and R26 together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;
7. Q2xe2x80x94L3, where
xe2x80x83Q2 is hydrogen or Q1; and
xe2x80x83L3 is a chemical bond or L1;
Q1 is an amino, amidino, aminoalkylenimino, iminoalkylenamino or guanidino group, preferably an amidino group;
L1 is C6-C14-aryl-C2-C4-alkynylene; C6-C14-aryl-C1-C3-alkylene; C6-C14-aryl-C1-C3-alkyloxyene or xe2x80x94R14cxe2x80x94COxe2x80x94NR6cR15c, where
R6c is hydrogen, C1-C4-alkoxy, C1-C4-alkyl or halogen-C1-C4-alkyl;
R14c is a chemical bond, C1-C8-alkylene, C3-C7-cycloalkylene, C2-C5-alkenylene, C3-C5-alkynylene, C6-C10-arylene, C1-C3-alkyl-C6-C12-arylene, C1-C2-alkyl-C6-C10-aryl-C1-C2-alkylene, C6-C10-aryl-C1-C2-alkylene or C6-C10-aryloxy-C1-C2-alkylene, and
R15c is a chemical bond, C1-C4-alkylene, C2-C4-alkenylene, C2-C4-alkynylene, C6-C10-arylene or C1-C3-alkyl-C6-C12-arylene;
or b) is a template from WO 95/04057, specifically: 
xe2x80x83where R1b, R2b, R25b and R26b are in this case:
R1b and R2b are, independently of each other, from one to three groups from the series consisting of hydrogen and halogen (fluorine, chlorine, bromine or iodine); and
R25b and R26b are, independently of each other hydrogen, C1-C10-alkyl, C3-C10-alkenyl, C6-C14-aryl or C1-C6-alkyl-C6-C10-aryl, or R25b and R26b together form a trimethylene, tetramethylene, pentamethylene or 3-oxopentamethylene radical;
or c) is a template from EP 0 655 439, specifically: 
or d) is a template from WO 94/12478, specifically: 
or e) is a template from WO 94/18981, specifically: 
xe2x80x83where Y3, V and Da are defined as described above;
or f) is a template from EP 0 531 883, specifically: 
xe2x80x83where:
Xxe2x80x2 is an oxygen, sulfur or nitrogen atom or an xe2x80x94NR2bxe2x80x94 group, where
R2b is a hydrogen atom, a straight-chain or branched alkyl group having from 1 to 15 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having in each case from 3 to 10 carbon atoms, where the double bond or triple bond cannot connect directly to the nitrogen atom, a cycloalkyl or cycloalkylalkyl group having in each case from 3 to 7 carbon atoms in the cycloalkyl moiety, an aryl group, an alkyl group having from 2 to 6 carbon atoms which is substituted, from the xcex2 position to the nitrogen atom of the xe2x80x94NR2bxe2x80x94 group onwards, by an R3bOxe2x80x94, (R3b)2Nxe2x80x94, R4bCOxe2x80x94NR3bxe2x80x94, alkylsulfonyl-NR3bxe2x80x94, arylsulfonyl-NR3bxe2x80x94, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl or R5b group, or an alkyl group having from 1 to 6 carbon atoms which is substituted by one or two aryl groups, R6bOCOxe2x80x94, (R3b)2NCOxe2x80x94, R5bxe2x80x94COxe2x80x94, R3bOxe2x80x94CO-alkylene-NR3bxe2x80x94COxe2x80x94, (R3b)2Nxe2x80x94CO-alkylene-NR3bxe2x80x94COxe2x80x94 or R5CO-alkylene-NR2xe2x80x94COxe2x80x94, group, in which R3b and R5b are defined as indicated below and R6b is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 5 to 7 carbon atoms or an aralkyl group,
Yxe2x80x2 is an NO-group, a nitrogen atom or a methine group which is optionally substituted by an alkyl group,
Z1, Z2, Z3 and Z4, which can be identical or different, are methine groups, carbon atoms, imino groups or nitrogen atoms, where at least one of the radicals Z1 to Z4 has to contain a carbon atom, and one or two methine groups which are adjacent to a nitrogen atom can in each case be replaced by carbonyl groups,
Z5 and Z6 are in each case a carbon atom, or else one of the radicals Z5 or Z6 is a nitrogen atom and the other of the radicals Z5 or Z6 is a carbon atom,
R3b is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, or an aryl, aralkyl, carboxyalkyl or alkoxycarbonylalkyl group,
R4b is a hydrogen atom, an alkyl or alkoxy group having in each case from 1 to 6 carbon atoms, or an aryl or aralkyl group having from 1 to 6 carbon atoms in the alkyl moiety, and
R5b is an azetidino, pyrrolidino, hexamethylenimino or heptamethylenimino group or a piperidino group in which the methyl group in the 4 position can be replaced by an oxygen atom, by a sulfenyl, sulfinyl or sulfonyl group, or by an imino group which is substituted by an R3b, R4bCOxe2x80x94, alkylsulfonyl or arylsulfonyl group, where R3b and R4b are defined as mentioned above;
F is a direct linkage, (C1-C6)-alkanediyl, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94COxe2x80x94, xe2x80x94Nxe2x80x94R2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2, xe2x80x94NRxe2x80x94S(O)2xe2x80x94, xe2x80x94CR2xe2x95x90CRxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94 which can in each case be substituted, once or twice, by (C1-C4)-alkyl; 
R2 and R3 are, independently of each other, H, (C1-C4)-alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkyl, phenyl or benzyl;
R4 is (C10-C14)-cycloalkyl, (C10-C14)-cycloalkyl-(C1-C4)-alkyl, or R16OR9, R16HNR9, R16NHC(O)OR9, R16S(O)nNHR9, R16OC(O)NHR9, R16C(O)NHR9, R16C(O)R9, R16NHC(O)R9 or R16NHS(O)nR9;
R5 is H, (C1-C6)-alkyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C4)-alkyl, trifluoromethyl, pentafluoroethyl, phenyl or benzyl;
R8 is H, (C1-C4)-alkyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C2)-alkyl, phenyl, benzyl, trifluoromethyl or pentafluoroethyl;
R9 is a direct linkage or (C1-C4)-alkanediyl;
R10 is C(O)R11;
R11 is OH, (C1-C6)-alkoxy, phenoxy, benzyloxy, (C1-C4)-alkylcarbonyloxy-(C1-C4)-alkoxy, NH2 or mono- or di-(C1-C6-alkyl) amino;
R12 is H, (C1-C4)-alkyl, trifluoromethyl, pentafluoroethyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkyl-(C1-C2)-alkyl, (C5-C6)-aryl, (C5-C6)-aryl-(C1-C2)-alkyl, H2N, R8R8NR9, R8NHC(O)R9, H2Nxe2x80x94C(xe2x95x90NH) or H2Nxe2x80x94C(xe2x95x90NH)xe2x80x94NHxe2x80x94;
xe2x80x83where two adjacent substituents R12 can together also be xe2x80x94OCH2Oxe2x80x94 or xe2x80x94OCH2CH2Oxe2x80x94;
R16 is (C10-C14)-cycloalkyl or (C10-C14)-cycloalkyl-(C1-C4)-alkyl which can optionally be substituted, once or twice, by (C1-C4)-alkyl, trifluoromethyl, phenyl, benzyl, (C1-C4)-alkoxy, phenoxy, benzyloxy, xe2x95x90O or mono- or di-((C1-C4)-alkyl)-amino, where the cycloalkyl radicals are preferably 1-adamantyl or 2-adamantyl, which can be substituted as described above;
n is 1 or 2; and
q is 0 or 1;
in all their stereoisomeric forms and mixtures thereof in all proportions, and their physiologically tolerated salts.
Preference is also given to compounds of the formula I, in which A, B, D, F and G are defined as above for the very particularly preferred compounds of the formula I and E is a template from WO 95/04057, EP 0655 439, WO 94/18981, WO 94/08962, EP 0668 278, WO 94/12478 or EP 0531 883, with the latter preferably being defined as above for the particularly preferred compounds of the formula I, and particularly preferably being defined as above for the very particularly preferred compounds of the formula I.
Another part of the subject-matter of the present invention is that a fibrinogen receptor antagonist, which is known per se, can be converted into a selective vitronectin receptor antagonist by replacing the basic group (together with spacer) of a fibrinogen receptor antagonist with Axe2x80x94Bxe2x80x94D, which is defined as in formula I, with the distance between R10 and the first N atom in A1 being from 12 to 13, and in A2 from 11 to 12, covalent bonds along the shortest route between these atoms.
In general, compounds of the formula I can be prepared, for example during the course of a convergent synthesis, by linking two or more fragments which can be derived retrosynthetically from the formula I. When preparing the compounds of the formula I, it can, in a general manner, be necessary, during the course of the synthesis, to use a protecting group strategy which is suited to the synthesis problem to temporarily block functional groups which could lead to undesirable reactions or side reactions in the particular synthesis step, as is known to the skilled person. The method of fragment linking is not restricted to the following examples but is generally applicable to syntheses of the compounds of the formula I.
For example, compounds of the formula I of the type
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94C(O)NR2xe2x80x94G,
in which F=C(O)NR2, can be prepared by condensing a compound of the formula II
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Mxe2x80x83xe2x80x83II,
where M is hydroxycarbonyl, (C1-C6)-alkoxycarbonyl or activated carboxylic derivatives, such as acid chlorides, active esters or mixed anhydrides, with HNR2xe2x80x94G.
In order to condense two fragments with the formation of an amide bond, use is advantageously made of the coupling methods, which are known per se, of peptide chemistry (see, for example, Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Volumes 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974). For this, it is, as a rule, necessary for non-reacting amino groups which are present to be protected with reversible protecting groups during the condensation. The same applies to carboxyl groups which are not involved in the reaction, which carboxyl groups are preferably employed as (C1-C6)-alkyl, benzyl or tert-butyl esters. There is no necessity to protect amino groups if the amino groups to be generated are still present as nitro or cyano groups and are only formed by means of hydrogenation after the coupling has taken place. After the coupling has taken place, the protecting groups which are present are eliminated in a suitable manner. For example, NO2 groups (guanidino protection), benzyloxycarbonyl groups and benzyl esters can be removed by hydrogenation. The protecting groups of the tert-butyl type are eliminated under acid conditions, while the 9-fluorenylmethyloxycarbonyl radical is removed using secondary amines.
Compounds of the formula I in which R10xe2x95x90SO2R11 are prepared, for example, by oxidizing compounds of the formula I in which R10xe2x95x90SH using methods which are known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E12/2, Georg Thieme Verlag, Stuttgart 1985, pp. 1058ff) to give compounds of the formula I in which R10xe2x95x90SO3H, from which the compounds of the formula I in which R10xe2x95x90SO2R11 (R11xe2x89xa0OH) are then prepared directly or by way of corresponding sulfonyl halides by means of esterification or formation of an amide bond. Oxidation-sensitive groups in the molecule, such as amino, amidino or guanidino groups, are, if necessary, protected with suitable protecting groups before performing the oxidation.
Compounds of the formula I in which R10xe2x95x90S(O)R11 are prepared, for example, by converting compounds of the formula I in which R10xe2x95x90SH into the corresponding sulfide (R10xe2x95x90Sxe2x8ax96) and then oxidizing with metachloroperbenzoic acid to give the sulfinic acids (R10xe2x95x90SO2H) (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, pp. 618f), from which the corresponding sulfinic acid esters or amides, R10xe2x95x90S(O)R11 (R11xe2x89xa0OH), can be prepared using methods which are known from the literature. In a general manner, other methods known from the literature can also be used to prepare compounds of the formula I in which R10xe2x95x90S(O)nR11 (n=1 or 2) (cf. Houben-Weyl, Methoden der organischen Chemie, Vol. E11/1, Georg Thieme Verlag, Stuttgart 1985, pp. 618ff or Vol. E11/2, Stuttgart 1985, pp. 1055ff).
Compounds of the formula I in which R10xe2x95x90P(O)(R11)n (n=1 or 2) are synthesized, using methods which are known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vols. E1 and E2, Georg Thieme Verlag, Stuttgart 1982), from suitable precursors, with it being necessary to match the selected synthesis method to the target molecule.
Compounds of the formula I in which R10xe2x95x90C(S)R11 can be prepared using methods known from the literature (cf. Houben-Weyl, Methoden der Organischen Chemie, Vols. E5/1 and E5/2, Georg Thieme Verlag, Stuttgart 1985).
Compounds of the formula I in which R10xe2x95x90S(O)nR11 (n=1 or 2), P(O)(R11)n (n=1 or 2) or C(S)R11 may, of course, also be prepared by means of fragment linking, as described above, which approach is, for example, advisable when, for example, a (commercially available) aminosulfonic acid, aminosulfinic acid, aminophosphonic acid or aminophosphinic acid, or derivatives derived therefrom, such as esters or amides, are present in Fxe2x80x94G of the formula I.
Compounds of the formula I in which A=A1=R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94C(O)xe2x80x94 or cyclic acylguanidines of the type 
can be prepared, for example, by reacting a compound of the formula III
Q(O)Cxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83III
in which Q is a leaving group which can readily be substituted nucleophilically, with the corresponding guanidine (derivative) of the type 
or the cyclic guanidine (derivative) of the type 
The activated acid derivatives of the formula III, in which Q is an alkoxy, preferably a methoxy, group, a phenoxy group, a phenylthio, methylthio or 2-pyridylthio group, or a nitrogen heterocycle, preferably 1-imidazolyl, are advantageously obtained, in a manner known per se, from the carboxylic acids (Qxe2x95x90OH) on which they are based or the carboxylic acid chorides (Qxe2x95x90Cl). The latter are in turn obtained, in a manner known per se, from the corresponding carboxylic acids (Qxe2x95x90OH), for example by means of reacting with thionyl chloride. In addition to the carbonyl chlorides (Qxe2x95x90Cl), other activated acid derivatives of the Q(O)C-type can also be prepared, in a manner known per se, directly from the corresponding carboxylic acids (Qxe2x95x90OH), such as the methyl esters (Qxe2x95x90OCH3) by treating with gaseous HCl in methanol, the imidazolides (Q=1-imidazolyl) by treating with carbonyldiimidazole [cf. Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)], and the mixed anhydrides (Qxe2x95x90C2H5OC(O)O or TosO) using Clxe2x80x94COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent. The carboxylic acids can also be activated with dicyclohexylcarbodiimide (DCCI) or with O-[(cyano(ethoxycarbonyl)methylen)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (xe2x80x9cTOTUxe2x80x9d) [Weiss and Krommer, Chemiker-Zeitung 98, 817 (1974)] and other activation reagents which are customary in peptide chemistry. A number of suitable methods for preparing activated carboxylic acid derivatives of the formula II are given, with citation of source literature, in J. March, Advanced organic Chemistry, Third Edition (John Wiley and Sons, 1985), p. 350.
An activated carboxylic acid derivative of the formula III is reacted with the relevant guanidine (derivative) in a manner known per se in a protic or aprotic, polar but inert organic solvent. In this context, methanol, isopropanol or tetrahydrofuran (THF), at temperatures of from 20xc2x0 C. up to the boiling temperature of these solvents, have proved to be of value when the methyl esters (Qxe2x95x90OMe) are reacted with the relevant guanidines. Most reactions of compounds of the formula III with salt-free guanidines are advantageously carried out in aprotic inert solvents such as THF, dimethoxyethane and dioxane. However, when a base (such as NaOH) is employed, water can also be used as solvent when compounds of the formula III are reacted with guanidines. When Qxe2x95x90Cl, the reaction is advantageously carried out in the presence of an added acid-capturing agent, for example in the form of excess guanidine (derivative), in order to bind the hydrohalic acid.
Compounds of the formula I, in which A=A1=R1R2Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94C(S)xe2x80x94 or 
can be prepared as described for the synthesis of corresponding open-chain or cyclic acylguanidine (derivatives) by reacting a compound of the formula XI
Q(S)Cxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83(XI)
in which Q is defined as above, with the corresponding guanidine (derivative) of the type 
or with the cyclic guanidine (derivative) of the type 
as described above.
Compounds of the formula I, in which A=A1 is a sulfonylguanidine or sulfoxylguanidine of the type R2R3Nxe2x80x94C(xe2x95x90NR2)xe2x80x94NR2xe2x80x94S(O)nxe2x80x94 (n=1 or 2) or 
are prepared, using methods which are known from the literature, by reacting R2R3Nxe2x80x94C(xe2x95x90NR3)NR2H or 
with sulfinic acid derivatives or sulfonic acid derivatives of the formula IV
Qxe2x80x94S(O)nxe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83IV
in which Q is, e.g., Cl or NH2, in analogy with S. Birtwell et al., J. Chem. Soc. (1946) 491 or Houben Weyl, Methoden der organischen Chemie, Vol. E4, Georg Thieme Verlag, Stuttgart 1983; pp. 620 ff.
Compounds of the formula I in which F is xe2x80x94R2Nxe2x80x94C(O)xe2x80x94NR2xe2x80x94 or xe2x80x94R2Nxe2x80x94C(S)xe2x80x94NR2xe2x80x94 are prepared, for example, by reacting a compound of the formula VII
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94NHR2xe2x80x83xe2x80x83VII
with an isocyanate OCNxe2x80x94G or isothiocyanate SCNxe2x80x94G using methods which are known from the literature.
Compounds of the formula I in which F is xe2x80x94C(O)NR2xe2x80x94, xe2x80x94SO2NR2xe2x80x94 or xe2x80x94C(O)Oxe2x80x94 can be obtained, for example, by reacting
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94C(O)Q or Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94SO2Q
(Q is a leaving group which can readily be substituted nucleophilically, such as OH, Cl, OMe etc.) with HR2Nxe2x80x94G or HOxe2x80x94G using methods known from the literature.
Compounds of the formula I, in which A=A2=
are prepared, for example, by condensing 
with ketones or aldehydes of the type Oxe2x95x90C(R2)xe2x80x94 or corresponding acetals or ketals using customary methods known from the literature, for example in analogy with N. Desideri et al., Arch. Pharm. 325 (1992) 773-777, A. Alves et al., Eur. J. Med. Chem. Chim. Ther. 21 (1986) 297-304, D. Heber et al., Pharmazie 50 (1995) 663-667, T. P. Wunz et al., J. Med. Chem. 30 (1987) 1313-1321, K. -H. Buchheit et al., J. Med. Chem. 38 (1995), 2331-2338.
The above guanyl hydrazones may result as E/Z isomeric mixtures, which can be resolved using customary chromatographic methods.
Compounds of the formula I, in which D is xe2x80x94Cxe2x89xa1Cxe2x80x94 can be prepared, for example, by reacting a compound of the formula IX
Xxe2x80x94Exe2x80x94Fxe2x80x94Gxe2x80x83xe2x80x83IX
in which X=I or Br, with a compound of the type Axe2x80x94Bxe2x80x94Cxe2x89xa1CH in a palladium-catalyzed reaction, for example as described in A. Arcadi et al., Tetrahedron Lett. 1993, 34, 2813 or E. C. Taylor et al., J. Org. Chem. 1990, 55, 3222.
In an analogous manner, compounds of the formula I in which F is xe2x80x94Cxe2x89xa1Cxe2x80x94 can be prepared, for example, by linking compounds of the formula X
Axe2x80x94Bxe2x80x94Dxe2x80x94Exe2x80x94Xxe2x80x83xe2x80x83X
in which X is I or Br, with a compound of the type HCxe2x89xa1Cxe2x80x94G in a palladium-catalyzed reaction.
The fibrinogen receptor antagonist template E is synthesized as described in the relevant patents, patent applications or publications, with functional groups being incorporated into the template, or being attached to the template, during synthesis of the template or afterwards, preferably during synthesis of the template, which groups permit the subsequent linking-on of Axe2x80x94Bxe2x80x94D and Fxe2x80x94G by means of fragment linking, as described below, by way of example, for a template from WO 94/18981: 
Example of the linking-on of Axe2x80x94Bxe2x80x94D and Fxe2x80x94G 
Preparation methods which are known from the literature are described, for example, in J. March, Advanced Organic Chemistry, Third Edition (John Wiley and Sons, 1985).
The compounds of the formula I, and their physiologically tolerated salts, may be administered to animals, preferably to mammals and, in particular, to humans, as drugs on their own, in mixtures with each other or in the form of pharmaceutical preparations which permit enteral or parenteral use and which comprise, as the active constituent, an effective dose of at least one compound of the formula I, or of a salt thereof, together with customary, pharmaceutically unobjectionable carrier and auxiliary substances. The preparations normally comprise from about 0.5 to 90% by weight of the therapeutically active compound.
The drugs may be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection or infusion solutions, microcapsules or rods, percutaneously, for example in the form of ointments or tinctures, or nasally, for example in the form of nasal sprays.
The pharmaceutical preparations are produced in a manner known per se, with pharmaceutically inert inorganic or organic carrier substances being used. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. can, for example, be used for preparing pills, tablets, coated tablets and hard gelatin capsules. Examples of carrier substances for soft gelatin capsules and suppositories are fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Examples of suitable carrier substances for preparing solutions and syrups are water, sucrose, invert sugar, glucose, polyols, etc. Suitable carrier substances for preparing injection solutions are water, alcohols, glycerol, polyols, vegetable oils, etc. Suitable carrier substances for microcapsules, implants or rods are mixed polymers of glycolic acid and lactic acid.
In addition to the active compounds and carrier substances, the pharmaceutical preparations may also comprise additives, such as fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, dyes, flavorants or aromatizing substances, thickeners, diluents or buffering substances, and also solvents or solubilizing agents or agents for achieving a slow release effect, and also salts for altering the osmotic pressure, coating agents or antioxidants. They may also comprise two or more compounds of the formula I or their physiologically tolerated salts; they may furthermore comprise one or more different therapeutically active compounds in addition to at least one compound of the formula I.
The dose may be varied within wide limits and must be adjusted to the individual circumstances in each individual case.
In the case of oral administration, the daily dose may be from 0.01 to 100 mg/kg, preferably from 0.1 to 5 mg/kg, particularly from 0.3 to 0.5 mg/kg of bodyweight in order to achieve effective results. Also in the case of intravenous administration the daily dose is generally from about 0.01 to 100 mg/kg, preferably from 0.05 to 10 mg/kg of bodyweight. Particularly when administering relatively large quantities, the daily dose can be subdivided into several, e.g. 2, 3 or 4, parts which are administered separately. Where appropriate, it can be necessary to depart from the given daily dose in an upward or downward direction depending on the individual response.
Besides as active drug substances the compounds of the formula I may be used in diagnostic procedures, for example in in vitro diagnoses, or as tools in biochemical research when it is intended to inhibit the vitronectin receptor.